Colorectal cancer afflicts 135,000 Americans per year and 38% of these patients will die of disseminated disease most commonly to liver lung and bone. Of the patients that die of this disease, 70% have liver metastases and a significant 10% have liver-only disease. Even in those patients with metastases to multiple organ sites, the extent of liver disease remains the primary determinant of survival. Over the last two decades we have empirically learned that patients with liver only metastases have improved survival when treated aggressively. Untreated, patients with hepatic only metastases have a median survival of only 12-21 months and the five year survival of patients with unresected metastasis is close to 0%. In sharp contrast, resection of metastases in patients with liver only disease yields five year survival rates of 20-40% and 10 year survival rates of 20%. Furthermore, the most common site of disease recurrence after resection is the liver. Consequently, liver metastases are a primary determinant of survival in patients with stage IV colorectal cancer. Building upon preliminary data linking ERBB receptor activity to colorectal cancer progression and metastasis, we hypothesize that small molecule ERBB inhibitors, if optimally employed, will retard the growth and dissemination of metastatic colorectal cancer. We also hypothesize that colorectal cancer can also arise independently of ERBB and that an understanding of these mechanisms will allow us to design better therapies. Thus, using a combination of clinical samples and pre-clinical mouse models, we propose to investigate the mechanism of how metastatic colon cancer uses EGFR and other ERBB receptor signaling to establish residency in the liver and to identify markers for response to dual EGFR/ERBB2 inhibitors during treatment of metastatic lesions. Experiments are planned to identify transcriptional profiles unique to EGFR independent colorectal cancer development.